To explore the mechanism of Zexie Decoction combined with Danshen Decoction in the treatment of atherosclerosis(AS) using network pharmacology and animal experiments.Methods:The effective components and target genes of the five drugs in Zexie Decoction combin0ed with Danshen Decoction were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and the Encyclopedia of Traditional Chinese Medicine(ETCM).A drug-component-target network diagram was constructed.Relevant AS disease targets were obtained from the GeneCards database and the Online Mendelian Inheritance in Man(OMIM) database，and the intersection targets were submitted to the STRING database to construct a protein-protein interaction(PPI) network.Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted using the Metascape database.The high-fat diet-induced AS rat model was established，and Zexie Decoction combined with Danshen Decoction was administered at low，medium，and high doses(6.3，12.6，25.2 g/kg) to verify the conclusions derived from network pharmacology.Results:Data mining identified 59 targets related to Zexie Decoction combined with Danshen Decoction and 1 187 AS-related target genes.Molecular docking revealed 63 intersecting targets.The core PPI network identified 62 key targets，including protein kinase B(AKT1)，tumor necrosis factor(TNF)，and interleukin 6(IL-6).KEGG enrichment analysis indicated that the key signaling pathway for treating AS with Zexie Decoction combined with Danshen Decoction was the phosphoinositide 3-kinase(PI3K)/AKT signaling pathway.Animal experiments confirmed that，compared to the model group，Zexie Decoction combined with Danshen Decoction significantly reduced blood lipids，inflammatory mediators such as IL-6 and C-reactive protein(CRP)，downregulated the expression of p-PI3K and p-AKT proteins in aortic tissue，and alleviated lipid-induced endothelial damage in the aorta.Conclusion:Zexie Decoction combined with Danshen Decoction may prevent and treat AS by regulating lipid metabolism，inhibiting inflammation，and modulating the PI3K/AKT signaling pathway.